Cancer development is associated with reactivation of several 'embryonic' signaling pathways, including the Hedgehog pathway, and our long-term goal in this grant has been to gain insight into how deregulated Hedgehog signaling contributes to tumor development. Our previous studies have been focused on basal cell carcinoma, a common skin tumor, and several other cancers associated with deregulated Hedgehog signaling. Activation of the Hedgehog (Hh)/Gli pathway in skin leads to formation of benign tumors called follicular hamartomas, basal cell carcinomas, or other follicular tumors. Both follicular hamartomas and basal cell carcinomas express multiple Wnt ligands, leading in both cases to activation of the canonical Wnt/beta-catenin pathway. While it has been shown that follicular hamartomas are strictly dependent on canonical Wnt/beta-catenin signaling for their formation, it is not known whether Wnt signaling plays a similarly important role in basal cell carcinomas and other malignant tumors driven by the Hh/Gli pathway. Although basal cell carcinoma tumor progenitors reside within the epithelial stem cell niche of the hair follicle, called the bulge, mobilization to form a transit amplifying cell population (a Wnt-mediated process) is required for tumorigenesis, underscoring the importance of a regenerative response in tumor development. We hypothesize that the phenotype of epithelial tumors arising in skin is determined by the nature of the oncogenic alteration(s), crosstalk with other signaling pathways, the location of potential tumor progenitors within their lineage, and tumor-promoting effects associated with tissue regeneration, either physiological (e.g., cyclical hair follicle growth) or pathological (wound-healing). We propose to begin exploring these relationships using state-of-the-art mouse models and a pharmacological inhibitor of Wnt signaling. In Aim 1 of this proposal, we will test the importance of canonical Wnt/beta-catenin signaling in the pathogenesis of basal cell carcinoma using genetic and pharmacological approaches. In Aim 2, we will determine the contribution of specific hair follicle cell compartments to Hedgehog/Gli-driven tumorigenesis, and assess the role of tissue regeneration in this process. In Aim 3, we will investigate the contribution of differentiated cell types to Hedgehog/Gli- and Ras-driven tumorigenesis in skin. These studies will yield new insights into the mechanisms underlying skin tumorigenesis, and are likely to lead to new approaches to the treatment of malignancies in which functionally relevant interactions exist between the Hh/Gli and Wnt pathways.